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Objective Our objective was to evaluate the effect of CYP2D6 phenotype in the enantioselective metabolism of tramadol in Spanish healthy human volunteers.

Methods A single oral 100 mg dose of racemic tramadol was administered to five subjects who were poor metabolizers (PMs) and 19 subjects who were extensive metabolizers (EMs), whose phenotypes were determined by the use of the racemic tramadol metabolic rate. The pharmacokinetic parameters were estimated from plasma concentrations of the enantiomers of tramadol and their main phase I metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol (M2). Epinephrine plasma concentrations were also determinated.

Results The plasma concentrations of both tramadol enantiomers were consistently higher in PMs than in EMs of CYP2D6, with 1.98- and 1.74-fold differences in the mean area under the plasma concentration–time curves (AUC), respectively. The values for oral clearance of (+)- and (?)-tramadol were 1.91- and 1.71-fold greater in PMs, which were related to differences in both O-desmethylation and N-desmethylation in the two CYP2D6 metabolizer phenotypes. The mean AUC values of (+)-M1 and (?)-M1 were 4.33- and 0.89-fold greater in EMs, and it was related to similar differences in the formation rate constant. On the other hand, the differences were 7.40- and 8.69-fold greater in PMs for M2 enantiomers due to the involvement of CYP2D6 in their subsequent biotransformation. The time course of epinephrine systemic concentrations was completely different between both groups of metabolizers. In EMs plasma concentrations of epinephrine increased after tramadol administration whereas in PMs no effect was observed.

Conclusions The polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol enantiomers. The N-desmethylation pathway was indirectly affected by CYP2D6 phenotypic differences. Epinephrine showed a good correlation with the pharmacokinetics of the opioid component of tramadol, (+)-M1 and was found to be useful for its pharmacodynamic profiling.